Mononuclear phagocytes constitute an important element of the host defenses against the development and spread of neoplasia. When macrophages are activated for cytolysis, they effectively and selectively lyse cancer cells by two distinct mechanisms (i.e., antibody-dependent kill and antibody-independent kill). The precise mechanisms responsible for target capture and cell-cell recognition in these, however, remain to be defined precisely. We have already provided data that macrophages have both antibody-independent and antibody-dependent mechanisms of recognition, that the development of stable cell-cell bonds which culminates in target lysis is an active rather than a passive process, and that requirements for stabilization of binding differ depending on whether the binding and recognition is antibody-independent or antibody-dependent. We therefore hypothesize that cell-cell recognition by activated macrophages is a complex, multi-step event, encompassing an initial step of weak target binding; subsequent initiation of metabolic events in the macrophages by engagement of the recognition system and stabilization of binding result from these metabolic events. We here propose to test this hypothesis critically and establish precisely what is required for stabilization of antibody-dependent and antibody-independent binding. Since we already have a great deal of information about the structure and function of both immunoglobulin molecules and Fc receptors on macrophages, our goals for this grant are to: 1) identify the molecules involved in antibody-independent binding; 2) analyze the actions and interactions of recognition molecules and macrophages leading to stabilization of antibody-dependent binding and 3) analyze the actions and interactions of macrophages and molecules that lead to stabilization of antibody-independent binding. These studies will define and characterize the means by which activated macrophages effect recognition of tumor cells. Elucidation of this important problem in immunopathology will amplify our understanding of how the mononuclear phagocyte system protects the host from various foreign invaders.
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